Novel Fluorite-Structured Materials for Solid-State Refrigeration.

Refrigeration based on the electrocaloric effect can offer many advantages over conventional cooling technologies in terms of efficiency, size, weight, and power source. The discovery of ferroelectric and antiferroelectric properties in fluorite-based materials in 2011 has led to diverse applications related to memory (e.g., ferroelectric tunnel junctions, nonvolatile memory, and field-effect transistors) and energy fields (e.g., energy storage and harvesting, electrocaloric refrigeration, and infrared detection). Fluorite-based materials exhibit several properties not shared by most conventional materials (such as in terms of compatibility with complementary metal-oxide semiconductors and 3D nanostructures, deposition thickness at the nanometer scale, and simple composition). Here, the electrocaloric refrigeration properties of fluorite-based ferroelectric/antiferroelectric materials are reviewed by focusing on the advantages of ZrO2 - and HfO2 -based materials (e.g., relative to conventional perovskite- and polymer-based counterparts). Finally, the recent progress made in this research field are also discussed along with its future perspectives.

Identification of Infigratinib as a Potent Reversible Inhibitor and Mechanism-Based Inactivator of CYP2J2: Nascent Evidence for a Potential In Vivo Metabolic Drug-Drug Interaction with Rivaroxaban.

Infigratinib (INF) is a fibroblast growth factor receptor inhibitor that was recently United States Food and Drug Administration-approved for the treatment of advanced or metastatic cholangiocarcinoma. We previously established that INF inhibited and inactivated cytochrome P450 3A4 (CYP3A4). Here, in a follow up to our previous study, we identified for the first time that INF also elicited potent competitive inhibition and mechanism-based inactivation of CYP2J2 with kinetic parameters K i, K I, k inact, and a partition ratio of 1.94 µM, 0.10 µM, 0.026 minute-1, and ∼3, respectively, when rivaroxaban was harnessed as the probe substrate. Inactivation was revealed to exhibit cofactor-dependency and was attenuated by an alternative substrate (astemizole) and direct inhibitor (nilotinib) of CYP2J2. Additionally, the nature of inactivation was unlikely to be pseudo-irreversible and instead arose from covalent modification due to the lack of substantial enzyme activity recovery after dialysis and chemical oxidation, as well as the lack of a resolvable Soret band in spectral scans. Glutathione trapping confirmed that the identity of the putative reactive intermediate implicated in the covalent inactivation of both CYP2J2 and CYP3A4 was identical and likely attributable to an electrophilic p-benzoquinonediimine intermediate of INF. Finally, mechanistic static modeling revealed that by integrating the previously arcane inhibition and inactivation kinetic parameters of CYP2J2-mediated rivaroxaban hydroxylation by INF illuminated in this work, together with those previously documented for CYP3A4, a 49% increase in the systemic exposure of rivaroxaban was projected. Our modeling results predicted a potential risk of metabolic drug-drug interactions between the clinically relevant combination of rivaroxaban and INF in the setting of cancer. SIGNIFICANCE STATEMENT: This study reported that INF elicits potent reversible inhibition and mechanism-based inactivation of CYP2J2. Furthermore, static modelling predicted that its coadministration with the direct oral anticoagulant rivaroxaban may potentially culminate in a metabolic drug-drug interaction (DDI) leading to an increased risk of major bleeding. As rivaroxaban is steadily gaining prominence as the anticoagulant of choice in the treatment of cancer-associated venous thromboembolism, the DDI projections reported here are clinically relevant and warrant further investigation via physiologically based pharmacokinetic modelling and simulation.

Metabolic Activation of the Acrylamide Michael Acceptor Warhead in Futibatinib to an Epoxide Intermediate Engenders Covalent Inactivation of CYP3A.

Futibatinib (FUT) is a potent inhibitor of fibroblast growth factor receptor (FGFR) 1-4 that is currently under clinical investigation for intrahepatic cholangiocarcinoma. Unlike its predecessors, FUT possesses an acrylamide warhead, which enables it to bind covalently to a free cysteine residue in the FGFR kinase domain. However, it remains uninterrogated if this electrophilic α, ß -unsaturated carbonyl scaffold could also directly or indirectly engender off-target covalent binding to nucleophilic centers on other cellular proteins. Here, we discovered that FUT inactivated both CYP3A isoforms with inactivator concentration at half-maximum inactivation rate constant, maximum inactivation rate constant, and partition ratios of 12.5 and 51.4 µ M, 0.25 and 0.06 minutes-1, and ∼52 and ∼58 for CYP3A4 and CYP3A5, respectively. Along with its time-, concentration-, and cofactor-dependent inhibitory profiles, FUT also exhibited several cardinal features that were consistent with mechanism-based inactivation. Moreover, the nature of inactivation was unlikely to be pseudo-irreversible and instead arose from the covalent modification of the cytochrome P450 apoprotein and/or its heme moiety due to the lack of substantial enzyme activity recovery following dialysis and chemical oxidation, as well as the absence of the diagnostic Soret peak in spectral analyses. Finally, utilizing glutathione (GSH) trapping and high-resolution mass spectrometry, we illuminated that while the acrylamide moiety in FUT could nonenzymatically conjugate to GSH via Michael addition, it was not implicated in the covalent inactivation of CYP3A. Rather, we surmised that it likely stemmed from the metabolic activation of its acrylamide covalent warhead to a highly electrophilic epoxide intermediate that could covalently modify CYP3A and culminate in its catalytic inactivation. SIGNIFICANCE STATEMENT: In this study, we reported for the first time the inactivation of CYP3A by futibatinib (FUT). Furthermore, using FUT as an exemplary targeted covalent inhibitor, our study revealed the propensity for its acrylamide Michael acceptor moiety to be metabolically activated to a highly electrophilic epoxide. Due to the growing resurgence of covalent inhibitors and the well-established toxicological ramifications associated with epoxides, we advocate that closer scrutiny be adopted when profiling the reactive metabolites of compounds possessing an α, ß -unsaturated carbonyl scaffold.

Acriflavine and proflavine hemisulfate as potential antivirals by targeting Mpro.

The evolving SARS-CoV-2 epidemic buffets the world, and the concerted efforts are needed to explore effective drugs. Mpro is an intriguing antiviral target for interfering with viral RNA replication and transcription. In order to get potential anti-SARS-CoV-2 agents, we established an enzymatic assay using a fluorogenic substrate to screen the inhibitors of Mpro. Fortunately, Acriflavine (ACF) and Proflavine Hemisulfate (PRF) with the same acridine scaffold were picked out for their good inhibitory activity against Mpro with IC50 of 5.60 ± 0.29 µM and 2.07 ± 0.01 µM, respectively. Further evaluation of MST assay and enzymatic kinetics experiment in vitro showed that they had a certain affinity to SARS-CoV-2 Mpro and were both non-competitive inhibitors. In addition, they inhibited about 90 % HCoV-OC43 replication in BHK-21 cells at 1 µM. Both compounds showed nano-molar activities against SARS-CoV-2 virus, which were superior to GC376 for anti-HCoV-43, and equivalent to the standard molecule remdesivir. Our study demonstrated that ACF and PRF were inhibitors of Mpro, and ACF has been previously reported as a PLpro inhibitor. Taken together, ACF and PRF might be dual-targeted inhibitors to provide protection against infections of coronaviruses.

Reusable Cu2-xS-modified masks with infrared lamp-driven antibacterial and antiviral activity for real-time personal protection.

Disposable surgical masks are widely used by the general public since the onset of the coronavirus outbreak in 2019. However, current surgical masks cannot self-sterilize for reuse or recycling for other purposes, resulting in high economic and environmental costs. To solve these issue, herein we report a novel low-cost surgical mask decorated with copper sulfide (Cu2-xS) nanocrystals for photothermal sterilization in a short time (6 min). With the spun-bonded nonwoven fabrics (SNF) layer from surgical masks as the substrate, Cu2-xS nanocrystals are in-situ grown on their surface with the help of a commercial textile adhesion promoter. The SNF-Cu2-xS layer possesses good hydrophobicity and strong near infrared absorption. Under the irradiation with an infrared baking lamp (IR lamp, 50 mW cm-2), the surface temperature of SNF-Cu2-xS layer on masks can quickly increase to over 78 °C, resulting from the high photothermal effects of Cu2-xS nanocrystals. As a result, the polluted masks exhibit an outstanding antibacterial rate of 99.9999% and 85.4% for the Escherichia coli (E.coli) and Staphylococcus aureus (S. aureus) as well as the inactivation of human coronavirus OC43 (3.18-log10 decay) and influenza A virus A/PR/8/34 (H1N1) (3.93-log10 decay) after 6 min irradiation, and achieve rapid sterilization for reuse and recycling. Therefore, such Cu2-xS-modified masks with IR lamp-driven antibacterial and antiviral activity have great potential for real-time personal protection.

An oxygenated perfluorocarbon emulsion improves liver graft preservation evaluated in DCD livers of male sprague dawley rats.

The application of perfluorocarbons, which can carry large quantities of oxygen, in organ preservation was limited by their poor solubility in water. A stable form of perfluorocarbon dispersed in suitable buffers is urgently needed. Perfluorocarbon emulsion was designed and characterized with respect to size distribution, rheology, stability, and oxygen-carrying capacity. The state of DCD rat donor livers preserved by the oxygenated perfluorocarbon emulsion was studied after ex vivo reperfusion by using biochemistry, pathology, and immunohistochemistry methods. Perfluorocarbon emulsion was successfully prepared by high-pressure homogenization. Optimized perfluorocarbon emulsion showed nanoscale size distribution, good stability, and higher oxygen loading capacity than that of HTK solution or water. The state of preserved livers after cardiac death rat liver was improved significantly after static cold storage for 48 hours in this oxygenated perfluorocarbon emulsion. The ATP content and down-regulation of HIF-1a expression after preservation of the liver graft by the oxygenated perfluorocarbon emulsion suggested the advantage of adequate oxygen supply for adequate time. This perfluorocarbon emulsion reported here might be considered a promising system for oxygenated donor liver storage by attenuation of hypoxia.

Microporous cellulosic scaffold as a spheroid culture system modulates chemotherapeutic responses and stemness in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) treatments are evaluated by two-dimensional (2D) in vitro culture systems, despite their limited ability to predict drug efficacy. The three-dimensional (3D) microporous scaffold provides the possibility of generating more reliable preclinical models to increase the efficacy of cancer treatments. The physical properties of a microporous cellulosic scaffold were evaluated. The cellulosic scaffold was biocompatible and had a highly porous network with appropriate pore size, swelling rate, and stiffness of cancer cell cultures. Cellulosic scaffolds were compared with 2D polystyrene for the culture of HepG2 and Huh7 human HCC cells. Cellulosic scaffolds promoted tumor spheroid formation. Cells cultured on scaffolds were more resistant to chemotherapy drugs and showed upregulation of EpCAM and Oct4. The migration ability of HCC cells cultured on scaffolds was significantly greater than that of cells grown in 2D cultures as evidenced by the downregulation of E-cadherin. In addition, the proportion of CD44+/CD133+ HCC cancer stem cells (CSCs) was significantly greater in cells cultured on scaffolds than in those grown in 2D cultures. These findings suggest that cellulosic scaffolds effectively mimic the in vivo tumor behavior and may serve as a platform for the study of anticancer therapeutics and liver CSCs.

MicroRNA-122 Inhibits Lipid Droplet Formation and Hepatic Triglyceride Accumulation via Yin Yang 1.

BACKGROUND/AIMS: An increase in intracellular lipid droplet formation and hepatic triglyceride (TG) content usually results in nonalcoholic fatty liver disease. However, the mechanisms underlying the regulation of hepatic TG homeostasis remain unclear. METHODS: Oil red O staining and TG measurement were performed to determine the lipid content. miRNA expression was evaluated by quantitative PCR. A luciferase assay was performed to validate the regulation of Yin Yang 1 (YY1) by microRNA (miR)-122. The effects of miR-122 expression on YY1 and its mechanisms involving the farnesoid X receptor and small heterodimer partner (FXR-SHP) pathway were evaluated by quantitative PCR and Western blot analyses. RESULTS: miR-122 was downregulated in free fatty acid (FFA)-induced steatotic hepatocytes, and streptozotocin and high-fat diet (STZ-HFD) induced nonalcoholic steatohepatitis (NASH) in mice. Transfection of hepatocytes with miR-122 mimics before FFA induction inhibited lipid droplet formation and TG accumulation in vitro. These results were verified by overexpressing miR-122 in the livers of STZ-HFD-induced NASH mice. The 3'-untranslated region (3'UTR) of YY1 mRNA is predicted to contain an evolutionarily conserved miR-122 binding site. In silico searches, a luciferase reporter assay and quantitative PCR analysis confirmed that miR-122 directly bound to the YY1 3'UTR to negatively regulate YY1 mRNA in HepG2 and Huh7 cells. The (FXR-SHP) signaling axis, which is downstream of YY1, may play a key role in the mechanism of miR-122-regulated lipid homeostasis. YY1-FXR-SHP signaling, which is negatively regulated by FFA, was enhanced by miR-122 overexpression. This finding was also confirmed by overexpression of miR-122 in the livers of NASH mice. CONCLUSIONS: The present results indicate that miR-122 plays an important role in lipid (particularly TG) accumulation in the liver by reducing YY1 mRNA stability to upregulate FXR-SHP signaling.

Engineering of Harobin for enhanced fibrinolytic activity obtained by random and site-directed mutagenesis.

We have previously published a report on the cloning and characterization of Harobin, a fibrinolytic serine protease. However, the broad application of this fibrinolytic enzyme is limited by its low expression level that was achieved in Pichia pastoris. To counteract this shortcoming, random and site-directed mutagenesis have been combined in order to improve functional expression and activity of Harobin. By screening 400 clones from random mutant libraries for enhanced fibrinolytic activity, two mutants were obtained: N111R, R230G. By performing site-directed mutagenesis, a Harobin double mutant, N111R/R230G, was constructed and can be functionally expressed at higher level than the wild type enzyme. In addition, it possessed much higher fibrinolytic and amidolytic activity than the wild type enzyme and other single mutants. The N111R/R230G expressed in basal salts medium was purified by a three step purification procedure. At pH of 6.0-9.0, and the temperature range of 40-90 °C, N111R/R230G was more active and more heat resistant. The fibrinolytic activities of Harobin mutants were completely inhibited by PMSF and SBTI, but not by EDTA, EGTA, DTT, indicating that Harobin is a serine protease. N111R/R230G showed much better anti-thrombosis effect than wild type Harobin and single mutants, and could significantly increase bleeding and clotting time. Intravenous injection of N111R/R230G in spontaneous hypertensive rats (SHR) led to a significant reduction in systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) (p < 0.01), while heart rate (HR) was not affected. The in vitro and in vivo results of the present study revealed that Harobin double mutant N111R/R230G is an appropriate candidate for biotechnological applications due to its high expression level and high activity in area of thrombosis and hypertension.

The Paranthrenini of mainland China (Lepidoptera, Sesiidae).

We here briefly review the Paranthrenini fauna of Mainland China and provide a checklist of 21 species for this region. We describe six new species: Paranthrene rubomacula Kallies & Owada sp. nov., Nokona opaca Kallies & Wang sp. nov., Nokona bractea Kallies & Arita sp. nov., Scoliokona nanlingensis Kallies & Arita sp. nov., Scoliokona spissa Kallies & Arita sp. nov., Scoliokona shimentai Kallies & Wu sp. nov. Furthermore, we provide numerous new combinations of species formerly associated with the genus Paranthrene in South East Asia, with 12 species transferred to Nokona Matsumura, 1931, 4 to Scoliokona Kallies & Arita, 1998, and one to Cyanosesia Gorbunov & Arita, 1995 (comb. nov.). The genus name Aritasesia Nakamura, 2009 (syn. nov.) is considered a junior subjective synonym of Nokona Matsumura, 1931. 

ROS-responsive MSC-derived Exosome Mimetics Carrying MHY1485 Alleviate Renal Ischemia Reperfusion Injury through Multiple Mechanisms.

Renal ischemia reperfusion (IR) injury is a prevalent inflammatory nephropathy in surgeries such as renal transplantation or partial nephrectomy, damaging renal function through inducing inflammation and cell death in renal tubules. Mesenchymal stromal/stem cell (MSC)-based therapies, common treatments to attenuate inflammation in IR diseases, fail to exhibit satisfying effects on cell death in renal IR. In this study, we prepared MSC-derived exosome mimetics (EMs) carrying the mammalian target of the rapamycin (mTOR) agonist to protect kidneys in proinflammatory environments under IR conditions. The thioketal-modified EMs carried the mTOR agonist and bioactive molecules in MSCs and responsively released them in kidney IR areas. MSC-derived EMs and mTOR agonists protected kidneys synergistically from IR through alleviating inflammation, apoptosis, and ferroptosis. The current study indicates that MSC-TK-MHY1485 EMs (MTM-EM) are promising therapeutic biomaterials for renal IR injury.

Preclinical characterization of GLS4, an inhibitor of hepatitis B virus core particle assembly.

Hepatitis B virus (HBV)-associated chronic liver diseases are treated with nucleoside analogs that target the virus polymerase. While these analogs are potent, drugs are needed to target other virus-encoded gene products to better block the virus replication cycle and chronic liver disease. This work further characterized GLS4 and compared it to the related BAY 41-4109, both of which trigger aberrant HBV core particle assembly, where the virus replication cycle occurs. This was done in HepAD38 cells, which replicate HBV to high levels. In vitro, GLS4 was significantly less toxic for primary human hepatocytes (P < 0.01 up to 100 µM), inhibited virus accumulation in the supernantant of HepAD38 cells (P < 0.02 up to 100 nM), inhibited HBV replicative forms in the liver with a significantly lower 50% effective concentration (EC50) (P < 0.02), and more strongly inhibited core gene expression (P < 0.001 at 100 to 200 nM) compared to BAY 41-4109. In vivo characterization was performed in nude mice inoculated with HepAD38 cells, which grew out as tumors, resulting in viremia. Treatment of mice with GLS4 and BAY 41-4109 showed strong and sustained suppression of virus DNA to about the same extents both during and after treatment. Both drugs reduced the levels of intracellular core antigen in the tumors. Alanine aminotransferase levels were normal. Tumor and total body weights were not affected by treatment. Thus, GLS4 was as potent as the prototype, BAY 41-4109, and was superior to lamivudine, in that there was little virus relapse after the end of treatment and no indication of toxicity.

UCN-01 induces S and G2/M cell cycle arrest through the p53/p21(waf1) or CHK2/CDC25C pathways and can suppress invasion in human hepatoma cell lines.

BACKGROUND: UCN-01 (7-hydroxystaurosporine), a protein kinase inhibitor, has attracted a great deal of attention as a potent antitumour agent. Several clinical trials of UCN-01 alone or in combination with other agents for different tumour types are currently underway, and some of these trials have had positive results. Hepatocellular carcinoma has high incidence rates and is associated with poor prognosis and high mortality rates. METHODS: Three different hepatoma cell lines (Huh7, HepG2, and Hep3B) were treated with different concentrations of UCN-01, and the anti-tumour effects of UCN-01 were evaluated. Following UCN-01 treatment, cell growth was measured using an MTT assay, cell cycle arrest was assayed using flow cytometry, and the mechanisms of cell cycle arrest and invasion inhibition were investigated through western blotting and a Matrigel invasion assay. RESULTS: After a 72-h UCN-01 treatment, the growth of different hepatoma cell lines was significantly inhibited in a dose-dependent manner, with IC50 values ranging from 69.76 to 222.74 nM. Flow cytometry results suggested that UCN-01 inhibits proliferation in the hepatoma cells by inducing S and G2/M phase arrest, but not G1/S arrest, which differs from previous reports that used other tumour cell lines. Western blot results illustrated that UCN-01 induces a G2/M phase arrest, regardless of the status of the p53/P21(waf1) pathway, whereas the CHK2/CDC25C pathway and the p53/p21(waf1)pathway were involved in the UCN-01-induced S phase arrest. UCN-01 remarkably inhibited Huh7 cell invasion in a time-dependent manner. Suppression of Huh7 cell invasion may be due to the down-regulation of phosphorylated ß-catenin by UCN-01. CONCLUSIONS: These findings suggest that UCN-01 induces hepatoma cell growth inhibition by regulating the p53/p21(waf1) and CHK2/CDC25 pathways. Suppression of Huh7 cell invasion by UCN-01 may be due to the down-regulation of phosphorylated ß-catenin. These data lend support for further studies on UCN-01 as a promising anti-HCC candidate.

Study on the Mechanical Behavior of a Dual-Density Hybrid Lattice Structure under Quasi-Static and Dynamic Compressions.

The dual-phase lattice structure composed of the matrix phase (MP) and the reinforcement phase (RP) is a novel hybrid lattice showing excellent energy absorption ability. However, the mechanical behavior of the dual-phase lattice structure under dynamic compression and the enhancement mechanism of the reinforcement phase have not been widely studied with the increase in compression speed. Based on the design requirements of dual-phase lattice materials, this paper combined octet-truss cell structures with different porosities, and the dual-density hybrid lattice specimens were fabricated via the fused deposition modeling technique. Under quasi-static and dynamic compressive loadings, the stress-strain behavior, energy absorption capacity, and deformation mechanism of the dual-density hybrid lattice structure were studied. The results showed that the quasi-static-specific energy absorption of the dual-density hybrid lattice structure was significantly higher than that of the single-density Octet lattice, and with the increase in compression strain rate, the effective specific energy absorption of the dual-density hybrid lattice structure also increased. The deformation mechanism of the dual-density hybrid lattice was also analyzed, and the deformation mode changed from an inclined deformation band to a horizontal deformation band when the strain rate changed from 10-3 s-1 to 100 s-1.

Intracellular Low Iron Exerts Anti-BK Polyomavirus Effect by Inhibiting the Protein Synthesis of Exogenous Genes.

BK polyomavirus (BKPyV) is a small double-stranded DNA virus and ubiquitous human pathogen that particularly affects immunocompromised individuals. Antiviral therapy for BKPyV is urgently needed. Intracellular irons have an important role in many viral infections, yet its contribution to BKPyV and replication has not been explored. In this study, we explored the interaction between BKPyV infection and intracellular iron and the inhibitory effect of iron depletion on BKPyV infection. By creating a low-intracellular-iron environment, we demonstrated that the iron-chelating-induced iron depletion inhibits BKPyV infection in primary renal tubular epithelial cells (RPTECs) and urinary bladder cancer cells (TCCSUP cells). Iron depletion exerts an inhibitory effect after BKPyV enters the nucleus, which might be due to the inhibition of the protein synthesis of exogenous genes in iron-depleted cells. Further exploration of the target proteins of iron-regulating viral infection could potentially be used to develop new strategies for urgently needed anti-BKPyV therapies. IMPORTANCE BKPyV poses a serious threat to the health of immunocompromised patients, and there are currently no curative drugs. Understanding the relationship between the virus and intracellular environment contributes to the discovery of antiviral targets. We demonstrate here that BKPyV is inhibited in cells with a low-iron environment. We also find that iron-chelating-induced iron depletion inhibits viral and exogenous protein synthesis. Further exploration of the target proteins of iron regulation could have great potential in developing new drugs against BKPyV and other viruses.

Survival analysis of patients with primary gallbladder cancer from 2010 to 2015: A retrospective study based on SEER data.

This study aims to assess the survival status of patients with Primary gallbladder cancer (PGC) and analyze the prognosis factors to facilitate the exploration of the prevention and therapeutic strategies of PGC.Data from 2433 PGC patients collected from 2010 to 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. The SEER*Stat, SPSS 23.0 and GraphPad Prism 8 were used for statistical analyses. Kaplan Meier analysis was performed for the survival curve, log-rank test analyses were used to compare the survival rate difference and Cox regression analyses were performed to determine the prognosis factors.A total of 2433 PGC cases were reported from 2010 to 2015. The median age was 64.2 ±â€Š10.4 years old and the percentages of the white patients were 73.7% (1794/2433). The percentage of patients who received surgery treatment was 82.1% (1998/2433). The overall median survival time of all patients was 19 months and the 5-year survival rate was 28.8%. The 5-year survival rate of PGC patients in pN2 stage dropped to 0% and the 5-year survival rate for PGC patients with distant metastasis was only 2.7%. Age, tumor size, grade, pT stage, pM stage were risk factors for prognosis, surgery or not and radiation or not were protective factors for prognosis.Survival analysis of PGC patients based on the SEER database have provided an opportunity for understanding PGC prognosis and the basis for the exploration of viable PGC prevention and therapeutic strategies.

Racial disparities in alpha-fetoprotein testing and alpha-fetoprotein status associated with the diagnosis and outcome of hepatocellular carcinoma patients.

BACKGROUND: The use of alpha-fetoprotein (AFP) testing for the surveillance, diagnosis, and prognosis of hepatocellular carcinoma (HCC) remains controversial. Here, we compared AFP testing rates, elevated AFP rates, factors associated with elevated AFP levels, and prognostic factors associated with overall survival (OS) in HCC patients from different ethnic groups. METHODS: Patients with HCC were identified from the Surveillance, Epidemiology, and End Results registries. Race was categorized as white, black, and others. AFP testing rates and elevated AFP rates were analyzed. Multivariable logistic regression and Cox regression analyses were used to identify independent factors associated with elevated AFP levels and prognosis, respectively. All statistical tests were two sided. RESULTS: A proportion of 79.2% of total HCC patients had AFP testing reports; 77.3% of white, 79.7% of black, and 81.2% of other races underwent AFP testing. Compared with white and other races, black HCC patients had a higher rate of elevated AFP levels among all patients and the early-stage HCC patient cohort. Elevated AFP level was a significant prognostic factor for all HCC patients in different race groups. Factors associated with elevated AFP level and prognostic factors associated with OS varied significantly by race. CONCLUSIONS: AFP testing, elevated AFP rates, predictors of elevated AFP level, and prognostic factors associated with OS differed significantly according to race after adjusting for AFP levels among the three groups. AFP testing for the surveillance, diagnosis, and prognosis of HCC patients is strongly recommended, although racial disparities need to be considered.

Importance of tumor size at diagnosis as a prognostic factor for hepatocellular carcinoma survival: a population-based study.

OBJECTIVE: The effects of hepatocellular carcinoma (HCC) tumor size on clinical presentation and treatment selection and its role as a prognostic factor remain unclear. The present study is a comprehensive analysis of the clinical correlation between tumor size at diagnosis and pathological grades, clinical staging, disparities of treatment, and survival of patients with HCC. MATERIALS AND METHODS: Patients with HCC were separated into groups according to tumor size as follows: 0.1-2.0, 2.1-5.0, 5.1-10.0, and 10.1-20.0 cm. Logistic regression analysis was used to determine the relationship between tumor size at diagnosis and pathological grade, Surveillance, Epidemiology, and End Results (SEER) historic stage A, and treatment selection. The survival of HCC patients stratified by tumor size was estimated by Kaplan-Meier and 5-year survival analyses using the log-rank test. Multivariable analysis of overall survival was performed using the Cox proportional hazards model. Tumor size at diagnosis was an independent risk factor of pathological grade, and SEER historic stage A was revealed by logistic regression analysis. RESULTS: The 5-year survival rate was 21.9% vs 14.3% vs 9.2% vs 7.7% for all HCC patients and 31.2% vs 23.6% vs 20.3% vs 15.5% for patients who underwent surgery with tumor sizes of 0.1-2.0 vs 2.1-5.0 and 5.1-10.0 vs 10.1-20.0 cm, respectively; multivariable Cox regression analysis identified tumor size at diagnosis as an independent predictor of survival risk with HR of 1.00 vs 1.66 vs 2.92 vs 3.67, respectively. CONCLUSION: Tumor size at diagnosis could be used as an independent risk predictor associated with histological grade, stage, selection of surgery, and survival in HCC.

Novel approaches towards conquering hepatitis B virus infection.

Currently approved treatments for hepatitis B virus (HBV) infection include the immunomodulatory agent, IFN-alpha, and nucleos(t)ide analogues. Their efficacy is limited by their side effects, as well as the induction of viral mutations that render them less potent. It is thus necessary to develop drugs that target additional viral antigens. Chemicals and biomaterials by unique methods of preventing HBV replication are currently being developed, including novel nucleosides and newly synthesized compounds such as capsid assembling and mRNA transcription inhibitors. Molecular therapies that target different stages of the HBV life cycle will aid current methods to manage chronic hepatitis B (CHB) infection. The use of immunomodulators and gene therapy are also under consideration. This report summarizes the most recent treatment possibilities for CHB infection. Emerging therapies and their potential mechanisms, efficacy, and pitfalls are discussed.

USP39 promotes colorectal cancer growth and metastasis through the Wnt/ß-catenin pathway.

In the present study, we first examined the expression of USP39 protein using tissue array containing 90 colorectal cancer (CRC) tissues and 9 clinical samples, and observed that it has significantly higher expression in cancer tissues as compared to the corresponding adjacent normal tissues. Also, we tested USP39 expression level in four CRC cancer cell lines and identified that it indeed had higher expression in all these CRC cell lines. In addition, its knockdown inhibited not only the cell growth of SW480 and HT29 cells, but also the cell migration and invasion. Further analysis of its molecular mechanism suggested that the expression of four crucial proteins of Wnt/ß-catenin pathway, including ß-catenin, TCF4, MMP2 and MMP9 was reduced as a result of USP39 knockdown. Taken together, all these findings demonstrated that USP39 protein plays an important role in the growth and metastasis of colorectal cancer mainly through Wnt/ß-catenin pathway.